RET Fusion

Overview

RET fusion refers to a rearranged form of the RET proto-oncogene in which the RET kinase domain becomes joined to a partner gene through chromosomal rearrangement. This creates an oncogenic fusion protein that can drive constitutive RET signaling and promote malignant transformation. RET fusions are recognized as actionable alterations in several cancers, particularly in subsets of non-small cell lung cancer and other solid tumors.

Biologically, RET fusion proteins are important because they can function as dominant oncogenic drivers, making them relevant both as biomarkers and as therapeutic targets. Their clinical significance has increased with the development of selective RET inhibitors, which aim to suppress RET-dependent tumor growth and downstream signaling pathways. Recent research has also explored RET-directed protein degradation strategies and resistance mechanisms, reflecting the continuing effort to improve treatment durability in RET fusion-positive disease.

Focus of Latest Publications

Recent publications have continued to define RET fusion as a clinically actionable target in RET-rearranged NSCLC and related malignancies. A major theme across these studies is the durability and limitations of selective RET inhibition. In the RET-MAP Registry, investigators examined retreatment with first-generation selective RET inhibitors in patients with RET-rearranged NSCLC who had previously received selpercatinib or pralsetinib. The study highlighted that treatment options after first-generation selective RET inhibitors are limited and that the value of RET inhibitor retreatment remains uncertain.

Clinical efficacy data were also updated in the phase I/II ARROW study of pralsetinib in advanced RET fusion-positive NSCLC. This report reinforced that RET fusions occur in approximately 1%–2% of NSCLCs and provided final efficacy and safety data for pralsetinib in this molecular subgroup. Related work in murine RET+ lung adenocarcinoma modeled acquired TKI resistance and evaluated combination therapeutic strategies, supporting the idea that resistance to RET-targeted therapy can be studied experimentally and may require rational combinations to restore control of tumor growth.

Several studies extended the RET fusion theme into broader oncologic contexts. A case report of pulmonary sarcomatoid carcinoma developing to small cell lung cancer suggested that TP53 and RET mutations may contribute to phenotypic transition, raising the possibility that RET-altered tumors can evolve under therapeutic or biologic pressure. Another report described RET-positive neuroendocrine lung cancer in pregnancy with placental metastases, emphasizing the rarity and clinical complexity of RET-driven neuroendocrine disease in this setting.

Mechanistic and translational studies also addressed RET signaling beyond classic fusion-positive lung cancer. One investigation showed that RET inhibition by selpercatinib suppresses TGF-β1-induced epithelial-mesenchymal transition (EMT) in retinal pigment epithelium, linking RET activity to EMT-associated cellular behavior. In thyroid cancer, studies of RET p.Cys634-driven progression in hereditary versus sporadic medullary thyroid cancer and a separate analysis of B7-H3 (CD276) as a candidate therapeutic target both noted that selective RET inhibitors have expanded treatment options, although disease progression still frequently occurs over time. These findings underscore the broader relevance of RET pathway biology in endocrine and neuroendocrine malignancies.

Drug development efforts remain active. A medicinal chemistry study described CN-3, a next-generation RET inhibitor designed to overcome multiple resistance mutations, explicitly noting that RET fusions and activating mutations drive multiple human cancers and that resistance mutations limit current selective RET inhibitors. Another study explored RET protein degradation using PROTAC and hydrophobic tag tethering degrader approaches, reflecting interest in strategies that go beyond kinase inhibition. Together, these reports position RET fusion as both a validated therapeutic target and a model for studying resistance, tumor evolution, and next-generation targeted therapy.

Key Publications

• NEWJul Retreatment with First-Generation Selective RET Inhibitors in RET-Rearranged NSCLC Pretreated with Selpercatinib or Pralsetinib: Results from the RET-MAP Registry. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41945500): "In RET-rearranged non-small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear."
• NEWJul Transformation or Clonal Evolution? A Rare Case Report of Pulmonary Sarcomatoid Carcinoma Developing to Small Cell Lung Cancer. (Thoracic cancer, 2026, PMID 42381179): "TP53 and RET mutations may be implicated in this phenotypic transition."
• Jul A GUV-based assay to reconstitute membrane tethering in vitro. (Molecular biology of the cell, 2026, PMID 42234594): "We demonstrate that: 1) GLT can be used to study liposome tethering, fusion, and phosphatase-mediated detethering of tethered liposomes."
• Mar Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma. (Cancer letters, 2026, PMID 41921856): "Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics."
• Jun B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer. (Endocrine-related cancer, 2026, PMID 42227355): "While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time."
• Jun RET inhibition by selpercatinib suppresses TGF-β1-induced epithelial-mesenchymal transition in retinal pigment epithelium. (Experimental cell research, 2026, PMID 41997282): "This study investigates the role of the receptor tyrosine kinase RET in TGF-β1-induced RPE-EMT."
• Jun RET p.Cys634-driven progression of hereditary vs. sporadic medullary thyroid cancer. (Endocrine, 2026, PMID 42257805): "This research sought to explore RET p.Cys634-driven tumorigenesis and progression which, preceding the time of clinical detection, cannot be measured directly."
• Jun Design, synthesis, and activity evaluation of RET protein degradation based on PROTAC and HyTTD techniques. (Bioorganic & medicinal chemistry letters, 2026, PMID 41692312): "Point mutations and fusions in the Rearranged during Transfection (RET) proto-oncogene are established drivers in diverse malignancies."
• Jun Impact of Bone Grafting and Graft Type on Fusion and Patient-Reported Outcomes Following Subtalar Arthrodesis: A Multicenter Retrospective Cohort Study. (Journal of foot and ankle research, 2026, PMID 42121338): "to evaluate the influence of different graft types on fusion and functional results."
• May RET-positive neuroendocrine lung cancer in pregnancy with placental metastases. (BMJ case reports, 2026, PMID 42173528): "Neuroendocrine lung tumours with RET point mutations have scarcely been reported in this setting."